Non-communicable mitochondrial diseases are becoming an increasing problem as population gets older and general life expectancy increases. Most often non-communicable mitochondrial diseases arise from some dysfunction of mitochondria itself or dysfunction in communication and cooperation of mitochondria and other cell organelles. These dysfunctions can lead to serious pathological conditions such as Alzheimer's disease, Parkinson's disease, cancer, cardiac disease, diabetes, epilepsy, Huntington's disease, and obesity. Mitochondrial matrix regulates through shuttle mechanisms cytosolic NAD+/NADH-ratio. Additionally in some physiological conditions it can also affect cytosolic NADPH/NADP+ ratio. Increased mitochondrial biogenesis has been proposed as one solution in replacing dysfunctional (damaged) old mitochondria with new properly functioning mitochondria.
Reactive oxygen species (ROS) or free radicals are produced intracellularly through multiple mechanisms and depending on the cell and tissue types, the major sources being NAD(P)H oxidase complexes in cell membranes, mitochondria, peroxisomes and endoplasmic reticulum. (NADPH is nicotinamide adenine dinucleotide phosphate in reduced form.) Mitochondria convert energy for the cell into a usable ATP form. The process in which ATP is produced, called oxidative phosphorylation, involves the transport of protons (hydrogen ions) across the inner mitochondrial membrane by means of the electron transport chain or better described as electron transport system. Various complexes related to the ETS are scattered on the inner membrane relatively randomly not as a “chain”. Complexes form a random system guided by greater reduction potential of next protein complex in the system, i.e. in the ETS electrons are passed through a series of proteins via oxidation-reduction reactions with each acceptor protein in the system having greater reduction potential than the previous. The last destination for an electron in this system is an oxygen molecule. Small part of electrons passing through the ETS escape, and oxygen is prematurely and incompletely reduced to give the superoxide radical. Superoxide is further converted e.g. to H2O2. ROS generation is most well documented for complex I and complex III.
ROSs are chemically reactive molecules containing oxygen. Examples include oxygen ions, peroxides and nitric oxide (NO). ROS form as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, during times of environmental stress (e.g., UV or heat exposure) or excessive metabolic stress, ROS levels can increase dramatically. This may result in significant damage to cell structures. Cumulatively, this is known as oxidative stress. ROS are also generated by exogenous sources such as ionizing radiation.
Normally, cells defend themselves against ROS damage with enzymes such as alpha-1-microglobulin, superoxide dismutases, catalases, lactoperoxidases, glutathione peroxidases and peroxiredoxins. Small molecule antioxidants such as ascorbic acid (vitamin C), tocopherol (vitamin E), uric acid, and glutathione also play important roles as cellular antioxidants. In a similar manner, polyphenol antioxidants assist in preventing ROS damage by scavenging free radicals. Antioxidant ability of the extracellular spaces, e.g. in plasma, is less efficient than intracellular ability. According to current knowledge the most important plasma antioxidant in humans is uric acid.
If too much damage is present in mitochondria, a cell undergoes apoptosis or programmed cell death. Bcl-2 proteins are layered on the surface of the mitochondria, detect damage, and activate a class of proteins called Bax, which punch holes in the mitochondrial outer membrane, causing cytochrome c to leak out. This cytochrome c binds to Apaf-1, or apoptotic protease activating factor-1, which is free-floating in the cell's cytoplasm. Using ATP as source of energy the Apaf-1 and cytochrome c bind together and form apoptosomes. The apoptosomes bind to and activate caspase-9, another free-floating protein. The caspase-9 then cleaves the proteins of the mitochondrial membrane, causing it to break down and start a chain reaction of protein denaturation and eventually phagocytosis of the cell.
Metabolic disorders are medical conditions characterized by problems with an organism's energy metabolism. Excessive nutrition and overweight are frequently related to a metabolic syndrome which has become a major health problem among humans. Metabolic syndrome is a combination of the medical disorders that, when occur together, increase the risk of developing cardiovascular disease and diabetes. Anabolic and catabolic reactions, regulatory hormones and proteins thereof are in a central position in the homeostasis of a human's metabolism. Fat and protein biosynthesis are examples of anabolic reactions. Aerobic degradation of carbohydrates, fats and carbon skeletons of amino acids represent a pathway, wherein oxygen is required in the last resort and which produces energy via the respiratory chain of the mitochondria. Coenzymes NAD+ (nicotinamide adenine dinucleotide, oxidized) and NADH (nicotinamide adenine dinucleotide, reduced), which regulate the redox state of a cell are in a central role in these processes. An excessive reduction of NAD+/NADH results in slow down of TCA, beta oxidation and glycolysis, and it can lead to cellular accumulation of AGEs (advanced glycation end-products). AGEs are proteins or lipids that become glycated after exposure to sugars and that cannot be used by normal metabolic pathways. AGEs are prevalent in the diabetic vasculature and contribute to the development of atherosclerosis.
In the transition to higher exercise intensity, the rate of adenosine triphosphate (ATP) hydrolysis is not matched by the transport of protons, inorganic phosphate and ADP into the mitochondria. Consequently, there is an increasing dependence on ATP supplied by glycolysis. Under these conditions, there is a greater rate of cytosolic proton release from glycolysis and ATP hydrolysis, the cell buffering capacity is eventually exceeded, and acidosis develops (Robergs, 2001). Increased capacity of cytosolic NAD+ providing mitochondrial shuttles can alleviate, postpone, and/or in some cases prevent acidosis.
U.S. Pat. No. 7,666,909 relates to enhancement of alcohol metabolism using D-glyceric acid. Eriksson et al., 2007 reported that administration of ethanol and D-glyceric acid calcium salt to rats expedited the metabolism of alcohol. In that scientific paper it was hypothesized that the activation of enzymes related to the metabolism of alcohol and acetaldehyde, i.e. alcohol dehydrogenase and acetaldehyde dehydrogenase, and reaction from D-glyceric acid to glycerol and simultaneous oxidation of 2 NAD+ molecules could possibly explain part of the acceleration in ethanol metabolism. Habe et al., 2011 showed in an in vitro study that D-glyceric acid can increase viability of ethanol-dosed gastric cells. Related to that article there seems to be also a patent that relates to alcohol induced gastrointestinal track mucous membrane damage and protection against it.
The existing solutions have been found to be ineffective in enhancing aerobic mitochondrial metabolism of carbohydrates, fats and amino acids as well as treating disorders related to metabolic disorders, especially outside of the gastrointestinal tract. Thus, there still exists a need to provide improved means and methods that are effective in the treatment and alleviation of metabolic.